EP3303312B1 - Verfahren zur herstellung von (e)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)-methanon-o-methyloxim - Google Patents

Verfahren zur herstellung von (e)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)-methanon-o-methyloxim Download PDF

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EP3303312B1
EP3303312B1 EP16753456.9A EP16753456A EP3303312B1 EP 3303312 B1 EP3303312 B1 EP 3303312B1 EP 16753456 A EP16753456 A EP 16753456A EP 3303312 B1 EP3303312 B1 EP 3303312B1
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methyl
benzofuran
dione
methanone
dihydro
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EP3303312A1 (de
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Vic PRASAD
Cameron Gibb
Christopher Lynn LARSON
A. Sai SRIKANTH
Jivan Dhanraj PAWAR
Sankar BALAKRISHNAN
K. N. Ravikumar
Avinash Shesharo MANE
Sagi SATEESH
Sampadarao Ananda RAO
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Arysta LifeScience Corp
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Arysta LifeScience Corp
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D273/00Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • C07D273/01Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 having one nitrogen atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D307/00Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present disclosure provides an improved process of preparing ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime, an intermediate useful for the synthesis of fluoxastrobin.
  • Fluoxastrobin is a strobilurin-type fungicidal active ingredient used for controlling fungal diseases such as early blight, late blight, leaf spots, leaf rust, and Rhizoctonia solani. Fluoxastrobin has been registered for foliar use on peanuts, tuberous and corm vegetables, leaf petiole vegetables, fruiting vegetables, and turf, as well as seed treatment for potato, peanuts, and turf. Turf applications are labeled for professional pest control operators.
  • Bayer provides a number of synthetic pathways to fluoxastrobin, although all proceed through a consecutive reaction of 4,6-dichloro-5-fluoro-pyrimidine with 2-chlorophenol and (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (4) as described in US 6,734,304 and shown below:
  • EP0846691 describes a process for preparing 3-(1-hydroxyphenyl-1-alkoximinomethyl)dioxazines, which are known as intermediates for preparing compounds having fungicidal properties.
  • EP0846691 also describes 3-(1-hydroxyphenyl-1-alkoximinomethyl)dioxazines compounds themselves, to intermediates for their preparation, and to processes for preparing the intermediates.
  • WO2015/006203 describes a process for preparing fluoxastrobin, including (i) reacting benzofuran-3( 2H )-one O-methyl oxime with an alkyl nitrite in the presence of an acid to form (3 E )-2,3-benzofuran-dione O 3 -methyl dioxime; (ii) reacting (3 E )-2,3-benzofuran-dione O 3 -methyl dioxime with 2-haloethanol to form (3 E )-benzofuran-2,3-dione O 2 -(2-hydroxyethyl) O 3 -methyl dioxime; (iii) reacting (3 E )-benzofuran-2,3-dione O 2 -(2-hydroxyethyl) O 3 -methyl
  • ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4) is an important intermediate in the synthesis of fluoxastrobin.
  • known methods of synthesis of ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O- methyl oxime are low yielding, include toxic reagents, and require lengthy and tedious work-up techniques and procedures, such as recrystallization and chromatography, which increase fluoxastrobin industrial production costs.
  • the present disclosure provides a process of preparing ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime by:
  • the disclosure includes a process for preparing ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (1):
  • the initial step in the disclosed process is the reacting of benzofuran-3(2 H )-one O -methyl oxime (1) with at least one nitrite selected from n-butyl nitrite and tert-butyl nitrite in the presence of a metal alkoxide to form (2Z,3Z)-2,3-benzofuran-dione O 3 -methyl dioxime (2) as the predominant isomer.
  • this reaction can be carried out by a number of nitrite reagents known in the art.
  • n-butyl nitrite CH 3 (CH 2 ) 3 NO 2 and tert-butyl nitrite (CH 3 ) 3 CNO 2 are particularly useful for effecting the desired transformation.
  • These reagents provide superior selectivity and better yields of (2 Z ,3 Z )-2,3-benzofuran-dione O 3 -methyl dioxime (2) compared to other nitrites.
  • n-butyl nitrite and tert-butyl nitrite are substantially less toxic than many other alkyl nitrites (for example, methyl nitrite CH 3 NO 2 ).
  • n-butyl nitrite or tert-butyl nitrite can be safely used when it is desired to selectively prepare (2 Z ,3 Z )-2,3-benzofuran-dione O 3 -methyl dioxime (2) from benzofuran-3(2 H )-one O -methyl oxime (1) on a large scale in a synthesis lab or an industrial setting.
  • the reaction of benzofuran-3(2 H )-one O -methyl oxime (1) with at least one nitrite selected from n-butyl nitrite and tert-butyl nitrite is carried out in the presence of an aprotic bipolar solvent, selected from N,N-dimethylformamide (“DMF”), dimethylsulfoxide (“DMSO”), or N-methyl-2-pyrollidone (“NMP”), or a combination thereof.
  • an aprotic bipolar solvent selected from N,N-dimethylformamide (“DMF”), dimethylsulfoxide (“DMSO”), or N-methyl-2-pyrollidone (“NMP”), or a combination thereof.
  • the reaction can be carried out by using N,N-dimethylformamide (“DMF").
  • the reaction of benzofuran-3(2 H )-one O -methyl oxime (1) with at least one nitrite selected from n-butyl nitrite and tert-butyl nitrite is carried out in the presence of a metal alkoxide.
  • the metal alkoxide can be lithium alkoxide, sodium alkoxide, potassium alkoxide, rubidium alkoxide, cesium alkoxide or a combination thereof, but is not limited thereto.
  • the metal alkoxide can be sodium alkoxide, potassium alkoxide, or a combination thereof.
  • Non-limiting examples of the sodium alkoxide include sodium methoxide (NaOCH 3 ) and sodium ethoxide (NaOCH 2 CH 3 ).
  • Non-limiting examples of the potassium alkoxide include potassium tert-butoxide (KOC(CH 3 ) 3 ).
  • the reaction typically starts by mixing a solution containing a nitrite reagent and metal alkoxide in a solvent with a solution of benzofuran-3(2 H )-one O -methyl oxime (1).
  • the mixing can take place at a temperature in a range of about 0°C to about 25°C, for example, about 0°C to about 5°C.
  • the reaction mixture is stirred at a temperature in a range of about 10°C to about 50 °C, for example, about 25°C to complete the reaction.
  • the reaction When the reaction is carried out in the presence of n-butyl nitrite or tert-butyl nitrite the reaction produces one mole of n-butanol or tert-butanol for each mole of (2 Z ,3 Z )-2,3-benzofuran-dione O 3 -methyl dioxime (2).
  • the pH of the reaction mixture is adjusted by an acid (for example, by sulfuric acid or hydrochloric acid), and the precipitated product is filtered.
  • the filtered product is washed with water to remove residual n-butanol or tert-butanol, unreacted metal alkoxide, impurities, and DMF.
  • the product is then dried to remove residual water to give (2 Z ,3 Z )-2,3-benzofuran-dione O 3 -methyl dioxime (2) as a solid.
  • the next step in the disclosed process is the reaction of (2 Z ,3 Z )-2,3-benzofuran-dione O 3 -methyl dioxime (2) with 2-haloethanol to form (2 Z ,3 Z )-benzofuran-2,3-dione O 2 -(2-hydroxyethyl) O 3 -methyl dioxime (3).
  • the reagent 2-haloethanol may include 2-chloroethanol, 2-bromoethanol, 2-iodoethanol, or a combination thereof.
  • the 2-haloethanol may be 2-chloroethanol.
  • ethylene oxide can be used instead of 2-haloethanol in the reaction.
  • 2-haloethanol is less toxic than ethylene oxide (which is a gas at ambient temperature) and can be easily manipulated on a large scale.
  • the reaction of (2 Z ,3 Z )-2,3-benzofuran-dione O 3 -methyl dioxime (2) with 2-haloethanol to form (2 Z ,3 Z )-benzofuran-2,3-dione O 2 -(2-hydroxyethyl) O 3 -methyl dioxime (3) is conducted in the presence of a solvent.
  • a solvent Any solvent suitable to carry out the reaction can be used.
  • an aprotic bipolar solvent such as N,N-dimethylformamide (“DMF"), dimethylsulfoxide (“DMSO”), or N-methyl-2-pyrollidone (“NMP”), but is not limited thereto is used.
  • the reaction can be carried out using N,N-dimethylformamide (“DMF").
  • the reaction of (2Z,3Z)-2,3-benzofuran-dione O 3 -methyl dioxime (2) with 2-haloethanol to form (2Z,3Z)-benzofuran-2,3-dione O 2 -(2-hydroxyethyl) O 3 -methyl dioxime (3) can be conducted in the presence of a base.
  • the base can be a metal carbonate, for example, lithium carbonate (Li 2 CO 3 ), sodium carbonate (Na 2 CO 3 ), potassium carbonate (K 2 CO 3 ), cesium carbonate (Cs 2 CO 3 ), but is not limited thereto.
  • the base can be potassium carbonate (K 2 CO 3 ).
  • the reaction produces one mole of potassium bicarbonate (KHCO 3 ) for each mole of the (2 Z ,3 Z )-benzofuran-2,3-dione O 2 -(2-hydroxyethyl) O 3 -methyl dioxime (3) formed.
  • the reaction is typically initiated by mixing (2 Z ,3 Z )-2,3-benzofuran-dione O 3 -methyl dioxime (2), 2-haloethanol, and the base in the solvent at a temperature in a range of about 0°C to about 35°C, for example, about 20°C to about 30°C.
  • the reaction mixture can then be agitated at the temperature of reagent mixing to complete the reaction.
  • the reaction mixture is usually heated at a temperature in a range of about 50°C to about 100°C, for example, about 75°C to about 80°C.
  • the reaction is typically quenched with water to precipitate the product from the solution.
  • the product is then collected by filtration and washed with water to remove solvent (such as DMSO), salt (such as potassium bicarbonate), unreacted 2-haloethanol, and unreacted base (such as potassium carbonate).
  • solvent such as DMSO
  • salt such as potassium bicarbonate
  • unreacted 2-haloethanol such as potassium carbonate
  • unreacted base such as potassium carbonate
  • the next step in the disclosed process is the reaction of (2 Z ,3 Z )-benzofuran-2,3-dione O 2 -(2-hydroxyethyl) O 3 -methyl dioxime (3) with an acid to form ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4):
  • the reaction can be carried out with hydrogen chloride (for example, hydrogen chloride gas), hydrogen bromide, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, or acetic acid.
  • hydrogen chloride for example, hydrogen chloride gas
  • hydrogen bromide sulfuric acid
  • methanesulfonic acid trifluoromethanesulfonic acid
  • trifluoroacetic acid trifluoroacetic acid
  • acetic acid By using acid as a catalyst, ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4) is prepared in high isomeric purity and excellent yield.
  • the ratio of ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime to ( Z )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime may be greater than 85:1, 90:1, 92:1, 95:1, 98:1, or 99:1.
  • the reaction of (2Z,3Z)-benzofuran-2,3-dione O 2 -(2-hydroxyethyl) O 3 -methyl dioxime (3) to ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4) is carried out in a solvent, which can be any solvent, stable to the action of an acid.
  • the reaction can be carried out in the presence of an ester solvent, such as ethyl acetate, propyl acetate, butyl acetate, but is not limited thereto.
  • the reaction can be carried out in the presence of butyl acetate.
  • the reaction typically starts by contacting a solution of (2 Z ,3 Z )-benzofuran-2,3-dione O 2 -(2-hydroxyethyl) O 3 -methyl dioxime (3) with an acid at a temperature in a range of about 0°C to about 25°C, for example, about 0°C to about 15°C and maintaining that temperature for a period of about 1 hour to about 24 hours, for example, about 4 hours to about 6 hours until (2 Z ,3 Z )-benzofuran-2,3-dione O 2 -(2-hydroxyethyl) O 3 -methyl dioxime (3) is consumed.
  • the mixture is typically diluted with water and the pH of the aqueous solution is adjusted to pH > 12 with a base, for example, sodium hydroxide.
  • a base for example, sodium hydroxide.
  • the organic impurities are then removed by extraction with a solvent.
  • the solvent used for the reaction can also be used for extraction.
  • the pH of the aqueous phase is lowered with an acid, for example, with acetic acid to crystallize ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4).
  • the product is then collected by filtration and washed with water to remove salts and impurities.
  • a distinguishing feature of the instantly disclosed process is that isolation of (2Z,3Z)-2,3-benzofuran-dione O 3 -methyl dioxime (2), (2 Z ,3 Z )-benzofuran-2,3-dione O 2 -(2-hydroxyethyl) O 3 -methyl dioxime (3), and ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4) is implemented by using simple filtration and does not require expensive, laborious, and time-consuming purification methods, such as recrystallization or chromatography.
  • benzofuran-3(2 H )-one O -methyl oxime (1) Methods of synthesis of benzofuran-3(2 H )-one O -methyl oxime (1) are known in the art.
  • benzofuran-3(2 H )-one O -methyl oxime (1) can be prepared as illustrated in Scheme 1.
  • methyl salicylate reacts with ethyl chloroacetate in the presence of potassium carbonate to give methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (7).
  • Hydrolysis of methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (7) followed by a consecutive cyclization of 2-(carboxymethoxy)benzoic acid (8) with acetic anhydride in the presence of sodium acetate gives benzofuran-3-yl acetate (9) which is converted to benzofuran-3(2 H )-one (10) by methanolysis.
  • Treatment of benzofuran-3(2 H )-one (9) with O -methylhydroxylamine and sodium acetate affords benzofuran-3(2 H )-one O -methyl oxime (1).
  • the disclosed process for preparing ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4) further comprises methods of preparing fluoxastrobin from the ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4).
  • the disclosure includes a method for preparing fluoxastrobin comprising: (iv) reacting a 4,6-di-halo-5-fluoro-pyrimidine (5), wherein X 1 is halogen, with ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4), optionally in the presence of a first solvent and optionally in the presence of a base, to form a ( E )-(2-((6-halo-5-fluoropyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O -methyl oxime (6):
  • the step of reacting a 4,6-di-halo-5-fluoro-pyrimidine (5), wherein each X 1 is halogen, with ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4) may be carried out in the presence of a tertiary amine, for example, 1,4-diazabicyclo[2.2.2]octane (“DABCO”), 1,5-diazabicyclo[4.3.0]non-5-ene (“DBN”), or 1,8-diazabicyclo[5.4.0]undec-7-ene (“DBU”), and for example, 1,4-diazabicyclo[2.2.2]octane (“DABCO").
  • DABCO 1,4-diazabicyclo[2.2.2]octane
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-
  • an amount of 1,4-diazabicyclo[2.2.2]octane may be from about 0.02 moles to about 0.4 moles per mole of the ( E )-(2-((6-halo-5-fluoropyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O -methyl oxime (4).
  • the amount of 1,4-diazabicyclo[2.2.2]octane is from about 0.02 moles to about 0.2 moles per mole of the ( E )-(2-((6-halo-5-fluoropyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O-methyl oxime (4).
  • Step (iv) is followed by reacting the ( E )-(2-((6-halo-5-fluoropyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O -methyl oxime (6) with 2-chlorophenol, optionally in the presence of a second solvent and optionally in the presence of a base, to form fluoxastrobin:
  • the first and second solvent may be the same or different.
  • Steps (iv) and (v) in the process for preparing fluoxastrobin may be carried out as a one-pot process, i.e. without isolation and purification of intermediate (6).
  • steps (iv) and (v) are carried out as a one-pot process, the first and second solvents are necessarily the same.
  • an amount of the 4,6-di-halo-5-fluoro-pyrimidine (5) may be from about 1 mole to about 4 moles per one mole of the ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4).
  • an amount of 2-chlorophenol may be from about 0.8 moles to about 4 moles per one mole of the ( E )-(2-((6-halo-5-fluoropyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O -methyl oxime (6).
  • the step of reacting a 4,6-di-halo-5-fluoro-pyrimidine (5), wherein X 1 is halogen, with ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (6) may be carried out at a temperature of about 0°C to about 100 °C, for example, about 40°C to about 80°C.
  • the reaction time may vary from about 1 hour to about 10 hours, for example, from about 1 hour to about 6 hours.
  • fluoxastrobin may be prepared from ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4) by
  • the solvent in steps (iv) and (v) for either method for preparing fluoxastrobin can be a ketone solvent, for example, methyl iso-butyl ketone (MIBK).
  • the base in steps (iv) and (v) of either method can be a metal carbonate, for example, potassium carbonate.
  • X 1 may be fluorine, chlorine, bromine, and iodine.
  • X 1 may be chlorine.
  • Steps (iv) and (v) of the process of either method for preparing fluoxastrobin may be carried out in the presence of a solvent.
  • the solvent may include a hydrocarbon solvent, a halogenated hydrocarbon solvent, an ether solvent, a ketone solvent, a nitrile solvent, an amide solvent, an ester solvent, a sulfoxide solvent, a sulfone solvent, water, or a combination thereof.
  • the hydrocarbon solvent may include an aliphatic solvent, an alicyclic solvent, an aromatic solvent, or a combination thereof.
  • Non-limiting examples of the hydrocarbon solvent include petroleum ether, pentane, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, 1,2-xylene, 1,3-xylene, 1,4-xylene, ethylbenzene, and cumene.
  • Non-limiting examples of the halogenated solvent include chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,1-trichloroethane, and 1,1,2-trichloroethane.
  • Non-limiting examples of the ether solvent include diethyl ether, diisopropyl ether, methyl-tert-butyl ether, methyl-tert-amyl ether, 1,4-dioxane, tetrahydrofuran ("THF”), 2-methyltetrahydrofuran, 1,2-dimethoxyethane (“DME”), and anisole.
  • the ketone solvent include acetone, 2-butanone, methyl isobutyl ketone, cyclopentanone, and cyclohexanone.
  • the ketone solvent may include methyl isobutyl ketone.
  • Non-limiting examples of the nitrile solvent include acetonitrile ("ACN”), propionitrile, n-butyronitrile, iso-butyronitrile, and benzonitrile.
  • Non-limiting examples of the amide solvent include N,N-dimethylformamide (“DMF”), N,N-dimethylacetamide (“DMA”), N-methylformamide, N-methylpyrrolidone (“NMP”), and hexamethylphosphoric triamide (“HMPA”).
  • Non-limiting examples of the ester solvent include methyl acetate and ethyl acetate.
  • Non-limiting example of the sulfoxide solvent include dimethyl sulfoxide (“DMSO”).
  • Non-limiting example of the sulfone solvent include sulfolane.
  • the solvent may be a mixture of the hydrocarbon solvent and the amide solvent.
  • the solvent may be a mixture of the aromatic hydrocarbon solvent and the amide solvent.
  • the aromatic hydrocarbon solvent in this mixture may include benzene, toluene, 1,2-xylene, 1,3-xylene, 1,4-xylene, ethylbenzene, and cumene.
  • the amide solvent may include N,N-dimethylformamide (“DMF”), N,N-dimethylacetamide (“DME”), N-methylformamide, N-methylpyrrolidone (“NMP”), and hexamethylphosphoric triamide (“HMPA”).
  • the solvent may be a mixture of the aromatic hydrocarbon solvent such as any xylene or toluene and the amide solvent, which may be for example, N,N-dimethylformamide (“DMF”), N,N-dimethylacetamide (“DME”), N-methylformamide, N-methylpyrrolidone (“NMP”), or hexamethylphosphoric triamide (“HMPA”).
  • the aromatic hydrocarbon solvent such as any xylene or toluene
  • amide solvent which may be for example, N,N-dimethylformamide (“DMF”), N,N-dimethylacetamide (“DME”), N-methylformamide, N-methylpyrrolidone (“NMP”), or hexamethylphosphoric triamide (“HMPA”).
  • DMF N,N-dimethylformamide
  • DME N,N-dimethylacetamide
  • NMP N-methylpyrrolidone
  • HMPA hexamethylphosphoric triamide
  • the solvent may be a mixture of the aromatic hydrocarbon solvent such as any xylene and the amide solvent, for example N,N-dimethylformamide (“DMF”), N,N-dimethylacetamide (“DME”), N-methylformamide, N-methylpyrrolidone (“NMP”), or hexamethylphosphoric triamide (“HMPA”).
  • the solvent may be a mixture of the aromatic hydrocarbon solvent such as toluene and the amide solvent such as N,N-dimethylformamide (“DMF”), N,N-dimethylacetamide (“DME”), N-methylformamide, N-methylpyrrolidone (“NMP”), or hexamethylphosphoric triamide (“HMPA”).
  • the base may include an inorganic base, an organic base, or a combination thereof.
  • the inorganic base may include a hydroxide, a hydride, an acetate, a carbonate, a bicarbonate, or a combination thereof.
  • Non-limiting examples of the inorganic base include sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydride, sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate.
  • Non-limiting examples of the organic base include trimethylamine, triethylamine, tributylamine, N,N-dimethylamine, N,N-di-iso-propylethylamine, N,N-dimethylbenzylamine, pyridine, 2-methylpyridine (2-picoline), 2,6-dimethylpyridine (2,6-lutidine), N-methylpiperidine, N-methylmorpholine (“NMM”), N,N-dimethylaminopyridine (“DMAP”), 1,5-diazobicyclo[4.3.0]non-5-ene (“DBN”), and 1,8-diazobicyclo[5.4.0]undec-7-ene (“DBU”).
  • the product is dried by passing air at 20-30°C for 60 min, and subsequently air dried at 70-85°C until the moisture content is NMT 1.0% w/w to give 2-(carboxymethoxy)benzoic acid (8) (548 g, 85%) as a solid.
  • IR (cm -1 ) 3060.43w, 1759.45s, 1577.24s, 1449.18s, 1361.45s, 1179.20s, 1090.38s, 890.75, 742.41.
  • IR (cm -1 ) 3070.02, 2898.40, 1604.89s, 1398.80s, 1537.36, 1465.17, 1041.49, 985.45s, 747.70s, 628.55s, 554.54s.
  • the mixture is warmed to 20-30°C, stirred for 4 h until the reaction is complete, and then cooled to 0-10°C.
  • H 2 O (7,105 mL) is added very slowly at 0-10°C to quench the reaction.
  • the pH of the mixture is adjusted to pH 1-2 using 50% aqueous H 2 SO 4 (665.76 g, 1.56 equiv.) while the temperature is maintained at 0-5°C.
  • the mixture is then stirred at 5-10°C for 30 min.
  • the pH of the reaction mixture is adjusted to pH >12 with an 11.13% solution of aqueous sodium hydroxide (2,461 g, 5.0 equiv.) while maintaining the temperature at 10-15°C.
  • the reaction mixture is stirred for 15 min and the phases are separated.
  • the product rich aqueous layer is washed with butyl acetate (2 ⁇ 1,470 mL) and the pH of the aqueous layer is adjusted to pH 5-5.5 using 50% aqueous acetic acid (323,5 g, 1.96 equiv.).
  • the resultant mixture is cooled to 0°C and stirred for 30 minutes to crystallize the product.
  • diethyl 2-chloromalonate may be performed by methods known in the art, for example by the method of Babu, G.R. et al. (Der Pharma Chemica (2011) 3(6):437-442 ).
  • Sulfuryl chloride is added to diethyl malonate at 60°C.
  • the molar ratio of sulfuryl chloride to diethyl malonate is approximately 1.2: 1.
  • the generated HCl and SO 2 gases are vented to the scrubber as they are formed.
  • the mixture is stirred for 6 h at 60°C and concentrated under reduced pressure to give diethyl 2-chloromalonate as a residue, which is carried forward without further purification.
  • Diethyl 2-chloromalonate is added to the mixture of triethylammonium hydrofluoride and triethylamine at 80-90°C under stirring. A molar excess of triethylammonium hydrofluoride and triethylamine to diethyl 2-chloromalonateis used. The resulting mixture is stirred at 100°C for 18 hours. The mixture is cooled and diluted with water. The product is extracted with xylene. The phases are separated and the organic phase is concentrated to give diethyl 2-fluoromalonate as a residue, which is carried forward without further purification.
  • a solution of diethyl 2-fluoromalonate in formamide is added to a solution containing a molar excess of sodium methylate in methanol heated at 65 °C for more than 4 hours.
  • water is added.
  • the mixture is acidified with hydrochloric acid to precipitate the product.
  • the product is collected by filtration, washed with water and thoroughly dried to give 5-fluoropyrimidine-4,6-diol (75%) as a solid.
  • 5-Fluoropyrimidine-4,6-diol is suspended in excess phosphorous oxychloride and the mixture is heated under stirring to 85°C for 4 hours until production of hydrogen chloride stops.
  • phosphorous trichloride is added over 15 min followed by an equimolar charge of chlorine gas over 1-2 hours.
  • the mixture is heated to 105-108°C and stirred until production of exhaust gases stops.
  • the mixture is concentrated to a residue to remove excess POCl 3 at the pressure of 150-200 mbar.
  • the residue is then distilled at 0.5 mbar pressure at approximately 40°C to give 4,6-dichloro-5-fluoropyrimidine (82%) as a liquid.
  • MIBK methyl iso-butyl ketone
  • DCFP 1,067 kg, 6.39 kmol
  • 2-chlorophenol 825 kg, 1.003 equiv.
  • water 4,4,000 L is added to the hot mixture to dissolve the formed salts.
  • the lower salt phase is transferred to waste water pre-treatment by pressure hydrolysis.
  • the remaining 4-chloro-6-(2-chlorophenoxy)-5-fluoropyrimidine (11) in MIBK is transferred to a storage tank for use in the final step.
  • isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium and isotopes of carbon include 11 C, 13 C, and 14 C.
  • halogen refers to fluorine, chlorine, bromine, or iodine.

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Claims (17)

  1. Verfahren zum Herstellen von (E)-(5,6-Dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanon-O-methyloxim, umfassend:
    (i) Umsetzen von Benzofuran-3(2H)-on-O-methyloxim (1) mit wenigstens einem Nitrit, ausgewählt aus n-Butylnitrit und tert-Butylnitrit, in der Gegenwart eines Metallalkoxids und eines aprotischen bipolaren Lösungsmittels, das N,N-Dimethylformamid, Dimethylsulfoxid, N-Methyl-2-pyrrolidon oder eine Kombination davon ist, um eine Zusammensetzung auszubilden, in der ein Isomer vorherrscht und (2Z,3Z)-2,3-Benzofurandion-O 3-methyldioxim (2) das vorherrschende Isomer ist;
    Figure imgb0036
    (ii) Umsetzen des (2Z,3Z)-2,3-Benzofuran-dion-O 3-methyldioxims (2) mit 2-Haloethanol, um (2Z,3Z)-Benzofuran-2,3-dion-O 2-(2-hydroxyethyl)-O 3-methyldioxim (3) auszubilden; und
    Figure imgb0037
    (iii) Umsetzen des (2Z,3Z)-Benzofuran-2,3-dion-O 2-(2-hydroxyethyl)-O 3-methyldioxims (3) mit einer Säure, um (E)-(5,6-Dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanon-O-methyloxim (4) auszubilden;
    Figure imgb0038
  2. Verfahren nach Anspruch 1, das zusätzlich umfasst:
    (iv) Umsetzen eines 4,6-Dihalo-5-fluor-pyrimidins (5), wobei X1 jeweils Halogen sind, mit (E)-(5,6-Dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanon-O-methyloxim (4), um ein (E)-(2-((6-Halo-5-fluorpyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanon-O-methyloxim (6) auszubilden:
    Figure imgb0039
  3. Verfahren nach Anspruch 2, das zusätzlich umfasst:
    (v) Umsetzen des (E)-(2-((6-Halo-5-fluorpyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanon-O-methyloxims (6) mit 2-Chlorphenol, um Fluoxastrobin auszubilden:
    Figure imgb0040
  4. Verfahren nach Anspruch 1, wobei die Säure Chlorwasserstoff ist.
  5. Verfahren nach Anspruch 1, wobei das Metallalkoxid Natriumalkoxid, Kaliumalkoxid oder eine Kombination davon ist.
  6. Verfahren nach Anspruch 1, wobei (2Z,3Z)-2,3-Benzofuran-dion-O 3-methyldioxim (2), (2Z,3Z)-Benzofuran-2,3-dion-O 2-(2-hydroxyethyl)-O 3-methyldioxim (3) und (E)-(5,6-Dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanon-O-methyloxim (4) isoliert werden und
    die Isolierung von (2Z,3Z)-2,3-Benzofuran-dion-O 3-methyldioxim (2), (2Z,3Z)-Benzofuran-2,3-dion-O 2-(2-hydroxyethyl)-O 3-methyldioxim (3) und (E)-(5,6-Dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanon-O-methyloxim (4) nicht die Rekristallisierung oder Chromatographie umfasst, und wobei die Reinheit des isolierten (E)-(5,6-Dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanon-O-methyloxim (4) 99 % oder mehr beträgt.
  7. Verfahren nach Anspruch 1, wobei die Isolierung von (2Z,3Z)-2,3-Benzofurandion-O 3-methyldioxim (2), (2Z,3Z)-Benzofuran-2,3-dion-O 2-(2-hydroxyethyl)-O 3-methyldioxim (3) und (E)-(5,6-Dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanon-O-methyloxim (4) bei einer Temperatur von 0 °C oder höher stattfindet.
  8. Verfahren nach Anspruch 3, wobei Schritt (iv) in der Gegenwart einer Base und eines ersten Lösungsmittels durchgeführt wird; Schritt (v) in der Gegenwart einer Base und eines zweiten Lösungsmittels durchgeführt wird; und die Schritte (iv) bis (v) in einem Eintopfverfahren durchgeführt werden und das erste und das zweite Lösungsmittel dasselbe sind.
  9. Verfahren nach Anspruch 1, wobei die Umsetzung des (2Z,3Z)-2,3-Benzofuran-dion-O 3-methyldioxim (2) mit 2-Haloethanol in der Gegenwart eines aprotischen bipolaren Lösungsmittels erfolgt.
  10. Verfahren nach Anspruch 9, wobei das aprotische bipolare Lösungsmittel N,N-Dimethylformamid, Dimethylsulfoxid, N-Methyl-2-pyrrolidon oder eine Kombination davon ist.
  11. Verfahren nach Anspruch 1, wobei der Gehalt des (2Z,3Z)-2,3-Benzofurandion-O 3-methyldioxim (2) in einem Gemisch aus (3E)- und (3Z)-Isomeren 94 % bis 98 % beträgt.
  12. Verfahren nach Anspruch 1, wobei die Umsetzung des (2Z,3Z)-Benzofuran-2,3-dion-O 2-(2-hydroxyethyl)-O 3-methyldioxim (3) mit einer Säure in einem Esterlösungsmittel durchgeführt wird, wobei das Esterlösungsmittel n-Butylacetat ist.
  13. Verfahren nach Anspruch 1, das zusätzlich folgendes umfasst:
    (v) Umsetzen von 4-Halo-6-(2-chlorphenoxy)-5-fluorpyrimidin (11) mit ((E)-(5,6-Dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanon-O-methyloxim (4), um Fluoxastrobin auszubilden:
    Figure imgb0041
  14. Verfahren nach Anspruch 2 oder Anspruch 13, wobei X1 Chlor ist.
  15. Verfahren nach Anspruch 2 oder nach Anspruch 14 in Abhängigkeit von Anspruch 2, wobei die Umsetzung des 4,6-Di-halo-5-fluor-pyrimidins (5) mit (E)-(5,6-Dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanon-O-methyloxim (4) in der Gegenwart eines tertiären Amins ausgeführt wird, das 1,4-Diazabicyclo[2.2.2]octan ist.
  16. Verfahren nach Anspruch 8 oder Verfahren nach einem der Ansprüche 13 und 14, wobei Schritt (v) in der Gegenwart eines Lösungsmittels und einer Base durchgeführt wird, wobei:
    das Lösungsmittel ein Ketonlösungsmittel ist; und/oder
    die Base ein Metallcarbonat ist.
  17. Verfahren nach Anspruch 16, wobei:
    das Lösungsmittel Methylisobutylketon (MIBK) ist; und/oder
    die Base Natriumcarbonat oder Kaliumcarbonat ist.
EP16753456.9A 2015-05-29 2016-05-10 Verfahren zur herstellung von (e)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)-methanon-o-methyloxim Active EP3303312B1 (de)

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DE10014607A1 (de) 2000-03-24 2001-09-27 Bayer Ag Verfahren zur Herstellung von unsymmetrischen 4,6-Bis(aryloxy pyrimidin-Derivaten
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AMIT KESHAV ET AL: "Reactive Extraction of Acrylic Acid Using Tri- n -butyl Phosphate in Different Diluents", JOURNAL OF CHEMICAL AND ENGINEERING DATA., vol. 54, no. 6, 11 June 2009 (2009-06-11), US, pages 1782 - 1786, XP055749161, ISSN: 0021-9568, DOI: 10.1021/je800856e *

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